IK1, also known as KCa3.1 or SK4, is a member of a family of small- to intermediate-conductance potassium channels in humans (SK1-3, IK1). IK1 plays a crucial role in T-cell activation by effluxing potassium to maintain a negative membrane potential that allows for additional calcium influx. IK1 is a potential therapeutic target (for inhibition) for autoimmune diseases and for organ transplant rejection. IK1 and SK1-3 are tetrameric and are gated/activated through calcium binding to calmodulin (CaM), which binds to a region within the cytoplasmic portion of the channels (CaM binding domain, CBD). A novel feature of IK1 activation is the additional requirement of phosphorylation of a specific histidine residue (His358) within the CBD by NDPK-B (nucleoside diphosphate kinase-B). Although histidine phosphorylation is well characterized in two-component signaling systems in prokaryotes, the extent and function of histidine phosphorylation in eukaryotes are just beginning to be understood. Recently, we hypothesized that histidine phosphorylation of IK1 is necessary to relieve metal- ion inhibition of the channel. In this application, biochemical, structural, and functional studies are proposed to elucidate the molecular mechanisms by which IK1 is regulated by calcium and histidine phosphorylation.

Public Health Relevance

The potassium channel IK1, also known as KCa3.1 or SK4, plays a crucial role in immunity by effluxing potassium ions from T cells during activation, which allows the influx of additional calcium ions. IK1 channel opening requires calcium binding to calmodulin, a protein that is bound to the cytoplasmic region of the channel. In addition, IK1 channel opening requires phosphorylation of a specific histidine residue in the cytoplasmic region of the channel, which is a novel regulatory feature for a mammalian protein. This proposal seeks to characterize in detail these two regulatory mechanisms of IK1. IK1 is a potential therapeutic target for autoimmune diseases and for organ transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI107443-01A1
Application #
9034760
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Singleton, Kentner L
Project Start
2016-01-01
Project End
2017-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$254,250
Indirect Cost
$104,250
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Ji, Tianyang; Corbalán-García, Senena; Hubbard, Stevan R (2018) Crystal structure of the C-terminal four-helix bundle of the potassium channel KCa3.1. PLoS One 13:e0199942
Srivastava, Shekhar; Panda, Saswati; Li, Zhai et al. (2016) Histidine phosphorylation relieves copper inhibition in the mammalian potassium channel KCa3.1. Elife 5: